DNMT3A R882H mutation promotes acute leukemic cell survival by regulating glycolysis through the NRF2/NQO1 axis

作者全名："Chu, Xuan; Zhong, Liang; Dan, Wenran; Wang, Xiao; Zhang, Zhonghui; Liu, Zhenyan; Lu, Yang; Shao, Xin; Zhou, Ziwei; Chen, Shuyu; Liu, Beizhong"

作者地址："[Chu, Xuan; Dan, Wenran; Wang, Xiao; Zhang, Zhonghui; Liu, Zhenyan; Lu, Yang; Shao, Xin; Zhou, Ziwei; Chen, Shuyu; Liu, Beizhong] Chongqing Med Univ, Yong Chuan Hosp, Cent Lab, Chongqing 402160, Peoples R China; [Zhong, Liang; Liu, Beizhong] Chongqing Med Univ, Dept Lab Med, Key Lab Lab Med Diagnost, Minist Educ, Chongqing 400016, Peoples R China"

通信作者："Liu, BZ (通讯作者)，Chongqing Med Univ, Yong Chuan Hosp, Cent Lab, Chongqing 402160, Peoples R China."

来源：CELLULAR SIGNALLING

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000944253900001

JCR分区：Q2

影响因子：4.4

年份：2023

卷号：105

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：AML; DNMT3A R882H mutation; Glycolysis; NRF2; NQO1 pathway; Daunorubicin

摘要："Background: Studies have confirmed that acute myeloid leukemia (AML) cells with DNA methyltransferase 3A Arg882His (DNMT3A R882H) mutation show an increased proliferation capability. However, the associated mechanism is still unclear. Glycolysis is involved in regulating malignant proliferation of cancer cell. Hence, we analyzed whether the DNMT3A R882H mutation interferes with glycolysis and thereby influences AML cell proliferation.Methods: We generated AML cell line carrying a DNMT3A-R882H mutation and compared it with the wild type (DNMT3A-WT) with regard to glycolysis regulation. Moreover, we analyzed the cell line's proliferation and apoptosis by a CCK-8 assay, western blotting, and flow cytometry. The role of NRF2/NQO1 signaling in regulating glycolysis was investigated by NRF2-knockdown and Brusatol (specific inhibitor of NRF2) treatment. Results: DNMT3A R882H cells had a higher glucose transport capacity compared to WT cells and their viability could be reduced by glucose deprivation. Moreover, daunorubicin had a slight inhibitory effect on glycolysis while glycolysis inhibition re-sensitized mutant cells to daunorubicin. Obviously, DNMT3A R882H mutation activated the NRF2/NQO1 pathway and enhanced the glycolytic activity in mutant cells. Conclusion: Taken together, these results suggest a novel mechanism by which a DNMT3A R882H mutation promotes glycolysis via activation of NRF2/NQO1 pathway. A parallel glycolysis inhibition adds to the anticancer effects of daunorubicin which might lead to a novel therapeutic approach for the treatment of AML patients carrying a DNMT3A R882H mutation."

基金机构：National Natural Science Foundation of China [81772280]; Graduate Scientific Research Innovation Project of Chongqing [CYB21189]; Chongqing Science and Technology Commission [csct2022ycjh-bgzxm0034]

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (Grant Number 81772280) , Graduate Scientific Research Innovation Project of Chongqing (CYB21189) and Chongqing Science and Technology Commission (csct2022ycjh-bgzxm0034) . The funding source provided financial support for the study and did not have any other involvement in this study."